Abstract Metal exposure has long been recognized as an environmental factor that contributes to the onset of neurodegenerative diseases. Chronic exposure to high levels of manganese (Mn) results in an extrapyramidal disorder referred to as manganism, characterized by cognitive, psychiatric and motor deficits resembling Parkinson's disease. At the cellular level, Mn impairs mitochondrial respiration, leading to energy failure and generation of reactive oxygen species (ROS). The autophagy-lysosome pathway is an essential component of intracellular degradation and quality control, and confers cytoprotection against neurodegeneration by timely removal of toxic proteins and dysfunctional mitochondria. It is widely accepted that autophagic dysfunction contributes to pathogenesis of various neurodegenerative disorders, but the role of autophagy in Mn-induced neurotoxicity has yet to be established. Our preliminary studies have shown that Mn exposure results in autophagic dysregulation both in vitro and in vivo. Pharmacological activation of autophagy ameliorated Mn-induced mitochondrial superoxide production and neuronal cell death, implicating autophagy failure in the etiology of Mn neurotoxicity. Furthermore, we found that Mn blocked nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy and lysosome-related genes. Our novel findings warrant further investigation of the mechanisms and functional role of autophagic dysfunction in Mn-induced neurotoxicity. Our proposal will test the hypothesis that Mn impairs autophagy by inhibiting TFEB activity, and that compromised autophagy contributes to the pathogenesis of Mn neurotoxicity. Specifically, in Aim 1, we will characterize the alterations in autophagic activity in a mouse model exposed to Mn. We also aim to determine the contribution of autophagy failure to Mn-induced neurotoxicity by examining whether restoring autophagy results in improved mitochondrial function and neurological outcomes. In Aim 2, we will establish the mechanistic link between loss of TFEB function and autophagy failure in Mn-induced neurotoxicity. We anticipate that the proposed study will provide novel information about cellular and molecular mechanisms underlying Mn-induced neuropathology, which may serve as a foundation for generating efficacious therapeutic strategies to combat Mn toxicity.